Yellow Fever Vaccine Booster Trial in Children- a Phase 3 Clinical Trial to Establish Safety and Immunogenicity of Repeated YF Vaccination in Healthy Gambian Children of Different Ages

1. Background information and rationale

1.2 Background information

Yellow fever (YF) virus is a mosquito-borne flavivirus found in Sub-Saharan Africa and tropical South America. The virus causes YF, a viral haemorrhagic fever, which can be prevented by a highly effective live-attenuated vaccine, however, it is now considered a re-emerging disease due to the increased numbers of cases in the last 30 years.

In most endemic countries across sub-Saharan Africa and South America, the YF vaccine is administered alongside other Expanded Programme on Immunization (EPI) vaccines, including the first measles containing vaccine (MCV1), at nine to 12 months of age. Several recent publications from Africa and Brazil have raised doubt that a single dose of YF vaccine will provide long lasting immunity: in a cohort vaccinated around nine-months of age in Ghana as part of a clinical trial of meningococcal vaccine, seropositivity, measured by microneutralization assay, had fallen from an already low 73%, 28 days following primary vaccination to 28% at 2.3 years . This figure had increased to 43% by six year - perhaps as a result of natural exposure or unrecorded re-vaccination. Our own data from samples collected in The Gambia and Mali 6 years post primary YF vaccinationadministered via the routine EPI program showed that 22.2% of a cohort of 467 children had undetectable antibody concentrations, with another 7.5% revealing concentrations below thethreshold of seropositivity of 0.5 IU/mL, confirming a substantial long-term decline in immunity relative to the early outcome of vaccination. Cross-sectional studies in Brazil, including nine month to 12-year olds, have similarly described a progressive decrease in the seropositivity rates from 87% within the first six-months after vaccination to 42% at six to eight years. It remains difficult to directly link the declining titres to actual occurrence of new cases of YF disease, as detailed immunisation history and in particular PRN titres are not available in observational studies of new cases, and no efficacy study has ever been performed. It is generally accepted though that high titres of YF antibodies protect against disease. The low residual titres in young children are therefore a legitimate cause for concern .

1.2 Rationale Despite the vaccine being very successful at decreasing disease risk, YF is considered a re-emerging disease due to the increased numbers of cases in the last 30 years . Until 2014, the vaccine was recommended to be administered with boosters every 10 years, but in 2014 the World Health Organization recommended removal of booster doses for all except special populations . This recommendation has been questioned and there have been reports of waning antibody titers in adults over time and more recently also in paediatric populations. The scarcity of long-term studies on neutralising antibodies elicited in vaccinated infants has been identified as a knowledge gap in regard to the need for booster doses of the yellow fever vaccine. Based on these emerging data, the investigators need to establish whether infants who received a primary dose of a yellow fever vaccine at nine months of age, in line with EPI recommendations, are indeed likely to require a booster dose of the vaccine in order to ensure long-term protection.